oligodendrocyte lineage cells seems to be af-
fected by neuronal activity ( 24 , 37 , 38 , 47 ),
consistent with neuronal activity playing a
regulatory function in myelin modulation, par-
ticularly in adulthood ( 36 – 39 , 49 ). However,
the role of myelin plasticity in brain functions
such as learning and memory is only now being
investigated.
Myelin plasticity in learning and memory
Our understanding of myelin function is
changing. Whereas it had been thought to
provide inert structural support, it is now
being viewed as a plastic and dynamic actor
of adaptive (and maladaptive) behavior, es-
pecially through its role in memory, defined
here as a change in circuit function caused by
an experience leading to a behavioral change
and learning ( 50 ).
MRI studies have revealed that when humans
learn new motor skills (e.g., juggling, playing the
piano) or cognitive skills (e.g., learning to read),
structural changes occur in the white-matter
tracts related to the fine-tuning of circuits ( 51 ).
A caveat of these studies is that the nature of
white-matter changes detected by structural
MRI techniques (such as fractional anisotropy,
an indication of white-matter microstructure)
is unclear, although it is assumed that these
changes are myelin-related ( 52 ). Nonetheless,consistent with the human data, rats that
undergo motor learning tasks show an in-
crease in fractional anisotropy on MRI scans,
which is associated with increased optical den-
sity of myelin basic protein (MBP) staining
in the white matter subjacent to the motor
cortex ( 53 ). Such studies provide some vali-
dation of the outcomes of MRI analyses and
support the hypothesis that changes in myelin
accompany learning and/or memory.
Studies capitalizing on the many advan-
tages of transgenic mice have sparked the
notion that de novo myelin formation may be
a form of brain plasticity similar to synapse
formation, which is generally accepted to be
a mechanism for learning, even though direct
experimental evidence has been difficult to
provide ( 54 ). The evidence that new oligoden-
drocytes are formed during the acquisition of
a new motor skill in mice, and the subsequent
demonstration that preventing OPC differen-
tiation into new myelinating oligodendrocytes
impairs behavioral performance in a wide ar-
ray of tasks (Fig. 3A) ( 41 , 55 – 57 ), further sup-
ports the hypothesis that myelin is causally
involved in learning and/or memory.OPC proliferation in learning and memory
Cross-sectional studies in mice consistently
report that OPC proliferation is fast, almost
immediate, upon initiation of training in a
behavioral task (Fig. 3) ( 42 , 55 , 56 ). In some
studies, the first time point tested was days
or weeks after training, making it difficult to
draw any firm conclusions about the exact
time course of OPC proliferation across tasks
and memory systems (Fig. 3B). Longitudinal
in vivo experiments indicate that OPC prolifer-
ation may reflect a homeostatic response to a
loss of OPCs ( 35 ). In fact, the overall number of
OPCs does not change during motor skill learn-
ing ( 58 ) and proliferation seems to be preceded
by OPC differentiation into premyelinating
oligodendrocytes ( 42 ) (Figs. 2A and 3B). These
premyelinating oligodendrocytes are not la-
beled by the proliferation marker ethynyl-2′-
deoxyuridine (EdU) ( 42 ), and as the majority
of OPCs directly differentiate after learning a
new motor skill, this indicates the presence
of primed OPCs ( 59 , 60 ) equipped to directly
differentiate, without proliferating first (Fig.
2A), upon changes in neuronal activity. This
structural plasticity occurs at a speed similar
to that of structural synaptic plasticity ( 61 ).
However, despite evidence for fast OPC prolif-
eration and early differentiation, detectable
changes in oligodendrogenesis (identified
as CC1+/ EdU+cells; Fig. 2A) do not appear
until days or weeks later (Fig. 3B) ( 41 , 42 ),
even though myelination can be a rapid pro-
cess [at least in the developing zebrafish ( 62 )].
Hence, oligodendrogenesis detected using this
method may indicate a second round of OPC
differentiation.Bonettoet al.,Science 374 , eaba6905 (2021) 12 November 2021 3of8
ABLong-term
Structural
PlasticityShort-term
Functional
Plasticity- Direct differentiation to
oligodendrocytes (EdU-) - Shed NG2 protein
(impacts synaptic plasticity)- Modifications of myelin
internodal length
- Modifications of myelin
- Regulate potassium levels
(impacting firing rate) - Metabolic support to maintain
fast neuronal firing rate - Removal/addition of
myelin internodes - Pruning of axon/pre-synapses
- Proliferation then differentiation
to oligodendrocytes (EdU+)
Proliferating
OPCPrimed
OPCPre-myelinating
oligodendrocyteMyelinating
oligodendrocyteNewly formed
oligodendrocyteSox10 / Olig2
NG2 / PDGFRaMAG/MOGCC1 (APC) / MBP / PLP / ASPAO4Enpp6
BCAS1Myrf Myrf MyrfEdUMyrf Myrf MyrfTa uDirect differentiationProliferationOPC oligodendrocyteNewly formed
Myelinating
oligodendrocyte- Potential role in circuit
function
(yet to be determined) - Potentially, secrete factors
that induce clustering of
nodal proteins on
unmyelinated axons - Secrete factors that induce
clustering of nodes
Fig. 2. From OPCs to myelinating oligodendrocytes.(A) Oligodendrocyte precursor cells (OPCs) differentiate
into myelinating oligodendrocytes in a multistep process dependent on the transcription factorMyrf.Cell markers
for each lineage stage and their approximate onsets/offsets are shown below the lineage progression diagram.
Emerging evidence suggests that OPCs can enter a primed state, mostly likely in G 1 phase arrest. These cells and
newly differentiated cells, marked by highEnpp6expression, are present in the brain and are ready to rapidly
differentiate further into premyelinating, and then myelinating, oligodendrocytes. Only proliferating OPCs incorporate
EdU (yellow nuclei), which fate-maps OPC differentiation into myelinating oligodendrocytes. Cells already past
the proliferative stage are not marked by EdU. (B) Table illustrating the forms of plasticity displayed by
oligodendrocyte lineage cells with implications for circuit plasticity, divided into long-term structural and short-
term functional plasticity. Abbreviations: EdU, ethynyl-2′-deoxyuridine; Myrf, myelin regulatory factor; Sox10,
SRY-box transcription factor 10; Olig2, oligodendrocyte transcription factor 2; NG2, neuron-glial antigen 2;
PDGFRa, platelet-derived growth factor receptor–a;Enpp6, ectonucleotide pyrophosphatase/phosphodiesterase 6;
BCAS1, brain-enriched myelin-associated protein 1; CC1, anti-adenomatous polyposis coli clone CC1; ASPA,
aspartoacylase; MBP, myelin basic protein; PLP, proteolipid protein 1; MAG, myelin-associated glycoprotein; MOG,
myelin oligodendrocyte glycoprotein. [Illustrations by K. Evans]
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